Lung Cancer 2 Flashcards
• PW is started on Osimertinib 80 mg po daily (EGFR pos mutation)
• What if PW was ALK mutation positive?
• What if PW was ROS1 mutation positive?
• What if PW was EGFR negative, ALK negative, ROS1 negative?
• What if PW progressed while on Osimertinib?
ALK mutation positive?
- alectinib
- check fo comorbidities
ROS1 mutation positive
- entrectinib (not for cognitive effects) or crizotinib
EGFR negative, ALK negative, ROS1 negative?
- talk abt things you can do with a platinum doublet, other target tx
• What if PW progressed while on Osimertinib?
- talk abt things you can do with a platinum doublet, other target tx
Programmed Cell Death 1 (PD-1/PD-L1) Inhibitors
Cancer can evade immune system
cnacer cells pushes the breaks with ligand on PD-1
PD-1 inhibitor block tumor cells from pushing the brakes
these help push brakes
there are 2 that can block the PD-1 and 2 that can block the ligand on the cancer cell
• Normal immune system has various “checkpoints”
to stop the immune system and hence prevent
over-activation
• PD-1 receptors
– an example of a checkpoint (“the brakes”)
– expressed on activated cytotoxic T cells
• PD-L1 (PD-1 Ligand)
– a ligand that can activate the checkpoint (“press on the brakes”)
– can be expressed on cancer cells
– allows a cancer cell to evade the immune system
• PD-1 Inhibitor Monoclonal Antibodies
– Nivolumab
– Pembrolizumab
• PD-L1 Inhibitor Monoclonal Antibodies
– Atezolimuab
– Durvalumab
PD-L1 Biomarker
• Pathology can measure the “Tumor Proportion Score” (TPS) for PD-L1
(PD-1 Ligand) in a tissue
– TPS = Percentage of viable tumor cells showing any PD-L1 staining
– TPS is VERY DIFFERENT than a somatic genetic mutation in the malignancy
• PD-L1 is not an optimal biomarker, but is currently the best biomarker
available to predict response to PD-1 or PD-L1 inhibitors
– In metastatic NSCLC, mostly helpful for predicting response to pembrolizumab
– Not as important for nivolumab, atezolizumab and durvaluma
Test to see how much pd-L1 is present
Percent of viable tumor cells showing they have the ligand
PD-1 and PDL-1 Immune Checkpoint Inhibitors
• PD-L1 expression is continuously variable and dynamic; thus a “cutoff“ value is somewhat arbitrary.
– Think of PD-L1 TPS score of >50% as being “high expression” or “good expression”
– Think of PD-L1 TPS score of >1% as “any expression”
• Pembrolizumab requires PD-L1 expression to be effective in NSCLC
– >50% required for first line monotherapy in NSCLC
– >1% required for second line monotherapy
- if more than 50 can give them just pembro, no chemo
• Nivolumab and Atezolizumab efficacy is less dependent on PD-L1 expression in NSCLC
– Both have been shown to still have benefit for disease progression after chemotherapy (SECOND LINE)even if PD-L1 expression is not detected.
• Regardless of PD-L1 expression levels, immunotherapy is less effective for tumours with driver
mutations (EGFR+, ALK+)
– If there is a driver mutation in metastatic disease, use the appropriate tyrosine kinase inhibitor first line!
Treatment mutation first
Cytotoxic T-Lymphocyte-Associated Antigen 4
(CTLA-4) Inhibitors
• B7 (on dendritic cells) binds to CD28 (on Tcells). This binding leads to a stimulatory signaling of the T cell causing T cell survival and proliferation.
• When B7 binds to CTLA-4 (a homolog of CD28) on the T-cell, a stimulatory signal is NOT
produced.
In other words CTLA-4 is another immune checkpoint
• Ipilimumab is a CTLA-4 inhibitor
- block that brake and enhance the go go go pathway for the T cells to do their thing
what if we do both
- block CD28 activation and take away PD-L1
- synergistic
Ipilimumab
CTLA-4
synergistic with PD1 targeting Mabs such as
Nivolumab
• There is data to support the combination of ipilimumab + nivolumab +/-chemotherapy (platinum doublet) in NSCLC
• In Alberta, the following is a funded treatment option
– Nivolumab 4.5 mg/kg (max 360 mg) IV q3wk up to 2 years and
– Ipilimumab 1 mg/kg IV q6wk up to 2 years and
– 2 cycles of platinum doublet chemotherapy
Always these 2 combined
PD-1 and PD-L1 Monoclonal Antibodies in Alberta
NOTE – Patients must have good PS (ECOG<2 ish)
Pembrolizumab
Nivolumab
Atezolizumab
Durvalumab
Nivo + ipi synergistic
Durv- only one for curative intent
Immune Mediated Adverse Effects
• Immune-Mediated Adverse Effects (IMAE) are a spectrum of
side effects cause by general immunologic enhancement
– Think about a medication induced autoimmune disease
• IMAE can be severe and even fatal if not recognized and
treated quickly
Approach to First Line Treatment in Advanced (stage
IIIB/C) or Metastatic non-squamous NSCLC
Is there a targetable mutation?
• If yes, use an appropriate targeted oral therapy (as funded)
Is patient good performance status and is there a high TPS score for PDL1?
• If >50%, then can use single agent pembrolizumab
Is patient good performance status? (ECOG <2ish)?
• Consider Chemotherapy + Immune Checkpoint Inhibitor Therapy
• Example: Ipilimumab + Nivolumab + Platinum Doublet
Is patient poor performance status?
• Consider less intensive therapy
• Example: Lower Dose chemotherapy and/or Radiation
Small Cell Lung Cancer (SCLC)
• Limited disease:
– cancer is contained in a single area that can be treated with radiotherapy
• cancer is only in one lung
• may be in nearby lymph Extensive disease
– If patient is fit, can be treated with curative intent
• Extensive disease
– cancer has spread beyond a single area
– It might have spread:
• to the other lung or to lymph nodes further away from the cancer
• Distant site (metastases)
• In pleural fluid (malignant pleural effusion)
– usually treated with palliative intent
• Highly linked to smoking
• SCLC is very RARE among non-smokers
• Grows quickly and spreads more easily than NSCLC
• Usually starts in cells that line the bronchi (centre of the lung)
• Limited Stage
• approximately 30% of SCLC
• Extensive Stage
• approximately 70% of SCLC
Small Cell Lung Cancer (SCLC)
prognosis
Stage 1:
• 3.5% of patient are diagnosed at stage 1
• 5 year survival is approximately 30%
• Evidence suggests that for smokers with early stage disease, 5 year
survival is approximately double if they quit smoking after diagnosis
Stage 4:
• 67% of patients are diagnosed at stage IV
• 5 year survival is 2%
• median survival is 7-11 months
Treatment of Limited Stage SCLC
– Concurrent Chemotherapy + Radiation
• For patients with good performance status (ECOG 0-1)
– Prophylactic Cranial Radiation
• If respond to chemotherapy
• Prophylaxis of brain metastases
Radiate the brain anyway in case of metasteses even tho it didnt show anything
Example Regimen for Limited Stage SCLC
Cisplatin 25 mg/m2 DAY 1, 2, 3 and Etoposide 100 mg/m2 DAY 1, 2, 3
Repeat every 21 days for 4-6 cycles
Radiation therapy usually beginning with cycle 2
smoking cessation
Treatment for Extensive Stage SCLC
Platinum Doublet
Chemotherapy 4-6
cycles + Duvalumab
Durvalumab
Maintenance
Regimens SCLC – repeat q21 days X 4-6 cycles
Cisplatin 75 mg/m2 DAY 1 and Etoposide 100 mg/m2 DAY 1, 2, 3
Cisplatin 25 mg/m2 DAY 1, 2, 3 and Etoposide 100 mg/m2 DAY 1, 2, 3
Carboplatin AUC 5 on DAY 1 and Etoposide 100 mg/m2 DAY 1, 2, 3
Combo of platnium +etoposid
Etoposide
• MOA: topoisomerase II inhibitor
• Can be given orally or IV
– Oral is approximately 50% bioavailable so dose of oral is usually increased
by a factor of 2 as compared to IV
• Side Effects:
– Hypotension during the infusion
– Allergic/hypersensitivity reactions (1%)
– Mucositis/Stomatitis
– Alopecia (hair loss)
– Bone marrow suppression (myelosuppression)
Oral or IV
Can see 1st day IV
Day 2-3 PO
Need to double dose for PO
Conclusion
• There are 2 main types of lung cancer; SCLC and NSCLC. NSCLC can be further divided
based on cell lineage and biomarker positivity.
• The treatment of NSCLC utilized many concepts of pharmacogenomics and precision
medicine in order to provide patients with the most appropriate treatment while
maintaining cost effectiveness
• Common agents used in lung cancer include: Cisplatin, Carboplatin, Etoposide,
Gemcitabine, Pemetrexed, Durvolumab, Osimertinib, Entrectinib, Alectonib, Crizotinib,
Brigatinib, Pembrolizumab, Nivolumab, Atezolizumab, Ipilimumab. These agents have
interesting MOA, unique dosing, and important toxicities.
• Smoking is the most important risk factor for developing lung cancer. For current smokers
that are diagnosed, smoking cessation is an important component of patient care.
